This Program Project is focused on examining the pathogenesis of experimental diabetic autoimmunity. Four investigators have coordinated and integrated their efforts, so to jointly gain an understanding of how T cells cause autoimmunity to beta cells. Drs. Emil Unanue and Osami Kanagawa have a joint project that examines the biochemical properties of the class II MHC molecule (I-Ag7) of the NOD mouse, the most important molecule required for the spontaneous development of diabetes. Their initial data indicates that I-Ag7 are weak peptide-binding class II molecules. project I evaluate the chemistry of I-Ag7, its binding properties and attempts to correlate these properties with T cell biology. The second project is by Dr. Jonathan Katz who has developed a T cell receptor bearing transgenic mice. The receptor is from a diabetogenic T cell clone reactive with a molecule of the beta cell granule. Dr. Katz has just published that skewing of these T cells towards a Th1 cytokine profile favors the development of diabetes. His present endeavors are to understand the transition from peri-insulitis to a diabetic stage, to examine how the state of T cell differentiation leads to pathology, to examine the effects of Th2 differentiation and the role of CD8 in diabetes, all of this using the powerful tool of a T cell receptor transgenic NOD mouse. Dr. Kenneth Murphy has been studying the molecular basis of Th1/Th2 differentiation, and has recently used another T cell receptor transgenic mice to follow their differentiation to Th1 or Th2 phenotype. Dr. Murphy proposes to examine the genetic basis of the response of undifferentiated T cells to Th1 or Th2 subset. He has definite evidence that unknown genes regulate the response to cytokines by altering the response to IL-12. Both Katz and Murphy argue that an understanding of the biology and molecular basis of T cell subset differentiation will be vital for the development, and control, of diabetic autoimmune reactions. All four investigators have projects that are truly synergistic and which will benefit from their joint efforts.